Retinoids are natural and synthetic derivatives of vitamin A (retinol) and have been recognized as physiologically important in cellular differentiation and proliferation. Retinoids are used extensively in the clinical treatment of a variety of dermatologic diseases and as chemotherapeutic anticancer agents. However, therapeutic doses can be teratogenic and cause embryonic death and fetal malformations in both humans and animals. Recent evidence suggested that the molecular mechanisms by which retinoids exert their teratogenic potential and physiological roles is through binding to nuclear retinoid receptors and altering gene expression. The retinoid receptors show structural homology and molecular mechanisms of action similar to the steroid-thyroid-vitamin D receptor superfamily. We have used the transient transfection of mammalian cells with a retinoic acid responsive reporter plasmid to study these mechanisms. The cotransfection of the plasmid expressing the catalytic subunit of cAMP-dependent protein kinase (PKA) revealed that the cAMP second messenger pathway of signal transduction is tightly coupled to the retinoid responsive pathway. We propose that retinoid receptors are natural substrates of PKA and this phosphorylation contributes to changes in gene expression. This hypothesis will be tested by: (i) confirmation of the phosphoamino acids in the RARs, (ii) in vitro mutagenesis to evaluate the effect of RAR phosphorylation on transcriptional activation, and (iii) the identification of other transcription factors, such as retinoid X receptor, that are regulated by PKA phosphorylation. These experiments should provide a better understanding of how two signalling pathways can elicit different responses depending on the participating transcriptional components in a cell. These observations may be applicable to a broad range of membrane receptors which are coupled to a second messenger system which can then interact with members of the intracellular steroid hormone receptor superfamily. It is expected that the results of our studies should provide the biomedical community with insights for better combined drug therapies.